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Department of Biochemistry, Medical School, University of Tasmania, Hobart 7001, Australia
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Microdialysis was used to assess the interstitial concentrations of glucose and lactate in the constant-flow-perfused rat hindlimb under varying levels of nutritive flow controlled by vasoconstrictors. Increased nutritive flow was achieved by norepinephrine (NE) or angiotensin II (ANG II) and decreased nutritive flow by serotonin (5-HT). NE and ANG II increased oxygen and glucose uptake as well as hindlimb lactate release by 50%. 5-HT decreased oxygen uptake by 15% but had no significant effect on glucose uptake or hindlimb lactate release. Microdialysis recovery of glucose and lactate was significantly elevated by NE and ANG II and decreased by 5-HT. The calculated interstitial concentration of glucose was increased by NE and ANG II but decreased by 5-HT. The interstitial concentration of lactate was decreased by NE and ANG II but increased by 5-HT. In all cases, nitroprusside reversed the effects of the vasoconstrictors. These data indicate that increased nutritive blood flow enhances the exchange of glucose and lactate by improving the supply of glucose to and the removal of lactate from the interstitium.
microdialysis; recovery; metabolism
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RECENT WORK IN THIS LABORATORY (for review, see Refs. 6, 8) has provided evidence for the existence of two vascular pathways in muscle. This supported the work of previous researchers who came to the same conclusion (3, 12, 17, 35). Flow through these two routes seems to be controlled by vasoconstrictors that can be classified into two groups according to their effects on muscle metabolism in the perfused rat hindlimb (6). Type A and type B vasoconstrictors act to increase and decrease metabolism, respectively (for review, see Refs. 6, 8). The vasoconstrictors do not affect total blood flow to the muscle as assessed by microsphere embolism (8), and both metabolic changes and pressure increases are reversed by vasodilators (9, 33). When muscles were isolated and incubated, however, the stimulatory (or inhibitory) metabolic effects of vasoconstrictors were absent (33, 34). Type A and B vasoconstrictors appear to redistribute microvascular flow within the muscle by increasing and decreasing nutritive flow, respectively (8). As a consequence, blood flow to the vessels supplying muscle cells is increased by type A vasoconstrictors (8, 28), whereas type B vasoconstrictors redirect flow from the muscle cells (8, 28) to vessels with a limited exchange capacity probably associated with the interfibrillar septa of muscle and with tendons (29). The distributions of the nutritive and nonnutritive routes are homogeneous throughout muscle, as evidenced by two recent studies (5, 41).
In the last decade, microdialysis has been used to monitor the interstitial concentrations of a variety of biologically important compounds in a range of tissues (4, 13). As an isotonic solution passes through the probe, compounds diffuse into and out of the probe in response to a concentration gradient. Changes in concentration emerging from the probe are indicative of changes in the interstitial concentration. It is often more useful, however, to determine the absolute interstitial concentration. The interstitial fluid is in direct contact with nonendothelial cells, and therefore its concentration is important in studies involving cellular metabolism. The two main methods used to determine interstitial concentration are the no-net flux and internal reference techniques and have been reviewed elsewhere (1, 2, 4). These techniques have been used to quantify the muscle interstitial concentration of a number of biologically important compounds including glucose (11, 16, 21, 26, 30) and lactate (16, 19, 21, 23, 26).
An important parameter in microdialysis studies is the recovery of the
probe. This is important because it represents changes in the net
movement of substances through the interstitial fluid. Recovery of a
particular compound is defined as
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(1) |
O/I,
recovery should vary directly with total blood flow and amount of
nutritive flow. In the case of metabolically active compounds, recovery
may also be affected by processes that represent another path for the
removal of compounds from the interstitial fluid, such as cellular
uptake (18, 39, 40). It may be hypothesized, therefore,
that the recovery of glucose and lactate should be increased by agents that increase nutritive flow and decreased by agents that increase nonnutritive flow. The aim of this study, therefore, was to determine the recovery and interstitial concentrations of glucose and lactate in
the perfused rat hindlimb under varying proportions of nutritive flow.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Eighteen male hooded Wistar rats (180-200 g) were cared for in accordance with the principles of the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (6th ed.; Australian Government Printing Services, Canberra, Australia, 1997). Rats were housed at 22°C with a 12:12-h light-dark cycle and were given free access to water and a commercial rat chow (20.4% protein, 4.6% lipid, 69% carbohydrate, and 6% crude fiber with added vitamins and minerals; Gibsons, Hobart, Australia). Anesthesia was administered by pentobarbital sodium (6 mg/100 g body wt ip) before all surgical procedures.
Microdialysis probes. Construction of the linear probes was previously described (27). Briefly, the point of a 23-gauge Terumo needle was blunted by filing, and the syringe adapter was removed. A 25-mm length of microdialysis tubing (Bioanalytical Systems; molecular mass cutoff 30 kDa; outer diameter 320 µm) was inserted into the blunt end of the needle to a depth of ~5 mm and glued with Araldite.
Hindlimb perfusions. Perfusions were conducted in a temperature-controlled cabinet set at 37°C. The perfusion medium was a modified Krebs-Henseleit buffer (in mM: 118 NaCl, 4.7 KCl, 1.2 KH2PO4, 1.2 MgSO4, 25 NaHCO3, and 8.3 glucose) containing 2.5 mM CaCl2, 1.2 mM pyruvate, 228 IU/l heparin, 4% bovine serum albumin, and washed bovine erythrocytes (35% hematocrit). Fresh bovine erythrocytes were washed three times in saline (0.9% NaCl) and twice in Krebs-Henseleit buffer and were stored in Krebs-Henseleit buffer at 4°C until use (erythrocytes were never >5 days old when used). Perfusate was gassed via a Silastic tube oxygenator with 95% air-5% CO2 and brought to 37°C by a heat exchanger coil. Both the arterial and venous perfusate passed through an arterio-venous (A-V) oxygen difference analyzer (A-VOX Systems, San Antonio, TX) that measures the spectral difference of arterial vs. venous blood at 660 nm (37). Arterial pressure and A-V difference in blood oxygen (in ml O2/100 ml blood) were recorded by the data acquisition program WinDaq (DATAQ Instruments, Akron, OH) at a sampling rate of 1 Hz.
Hindlimb surgery was essentially as described previously (36) with modifications as previously given (10). Flow was restricted to the left hindlimb by ligation of the right common iliac artery and vein. Also during the surgery, a small area of skin over the gastrocnemius and tibialis muscles was removed. Two microdialysis probes were inserted into the muscle as previously described (27). Postmortem dissection showed that the probe consistently traversed the tibialis, extensor digitorum longus, plantaris, and gastrocnemius muscles. During equilibration of the hindlimb preparation, the microdialysis probes were connected to a syringe pump and flushed at 100 µl/min with 200 µl of saline (0.9% NaCl) containing 8.3 mM [U-3H]glucose (400 nCi/ml) and 2.5 mM [14C]lactate (80 nCi/ml). For the remainder of the experiment, the syringe pumps were set at 2 µl/min. The hindlimb was allowed to equilibrate for 40 min at 4 ml/min. Microdialysis samples were collected for 20 min into narrow preweighed microcentrifuge tubes, at which point arterial and venous samples were collected. Pharmacological agents were dissolved in saline vehicle (0.9% NaCl) at 1,000 times the final concentration and were infused at 4 µl/min (1/1,000 of the perfusion flow rate). Norepinephrine (NE, final concentration 100 nM), angiotensin II (ANG II, 10 nM), serotonin (5-HT, 500 nM), or vehicle (saline, 0.9% NaCl) was infused into the arterial perfusate. The doses of NE and ANG II chosen give a similar oxygen uptake [higher perfusion pressure for NE may have resulted from additional spillover to receptors for type B vasoconstriction (6)]. After the pressure and oxygen had stabilized, a further 20 min was allowed to ensure that the microdialysis had fully equilibrated with the new state with respect to glucose and lactate. Microdialysis samples were then collected for another 20 min, and arterial and venous perfusate samples were taken. The vasodilator nitroprusside (NP, final concentration 10 µM) was added to the arterial perfusate, and the preparation was allowed to equilibrate for 20 min after the pressure and oxygen had stabilized. This concentration was chosen to ensure that there was no potential for increased glucose uptake with NP, as has been reported with millimolar doses (15). Final microdialysis samples were taken for 20 min as well as arterial and venous samples. The total number of perfusions conducted was 18 divided into 5, 5, 4, and 4 for vehicle, NE, ANG II, and 5-HT, respectively. This corresponded to 10, 10, 8, and 8 probes for vehicle, NE, ANG II, and 5-HT conditions, respectively.Sample analysis. Arterial and venous samples were analyzed for glucose and lactate on whole blood as well as plasma (Yellow Springs Instrument glucose/lactate analyzer). Microdialysis samples (including the inflow dialysis solution) were also analyzed for glucose and lactate (Yellow Springs Instrument glucose/lactate analyzer). The tubes were then reweighed to determine the remaining dialysate volume. These, as well as a known volume of the inflow solution, were put into 5-ml vials containing 3 ml of scintillant, and the vials were counted for 14C and 3H in a Beckman counter (LS 6500).
Calculations and statistics.
At required time points, perfusion pressures (mmHg) were taken directly
from the WinDaq trace. A-V oxygen difference (ml O2/100 ml
blood) taken from the WinDaq trace was converted into milliliters of
O2 per liter of blood and divided by 25.4 ml
O2/mmol (the volume-to-mole ratio of an ideal gas at
37°C). The A-V concentration differences (mM) for oxygen, glucose,
and lactate were converted into micromoles per hour per gram of muscle
by multiplying by the perfusion flow rate
(ml · h
1 · g muscle1).
Cin). The internal reference technique was used to
determine the interstitial concentration for glucose and lactate
because it has been found to give the same results as the no-net flux
technique (20). Briefly, the microdialysis recovery for
glucose and lactate was determined by the relative loss of
[3H]glucose and [14C]lactate, respectively,
according to Eq. 1. This is the special form of the equation
for recovery when the interstitial concentration is zero. The general
recovery equation is
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(2) |
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Figure 1 shows typical traces for
pressure and oxygen data in response to the vasoconstrictors or saline
and reversal by NP as well as sampling times for microdialysis and
arterial and venous perfusate.
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The combined data for perfusion pressure, oxygen uptake, glucose
uptake, and lactate efflux from all perfusions are shown in Fig.
2. The data for perfusion pressure and
oxygen uptake were taken at the same time as the arterial and venous
samples for glucose and lactate. This was found to give the same
average result as taking the mean of perfusion pressure and oxygen
uptake over the 20-min microdialysis sampling period. The two type A
vasoconstrictors (NE and ANG II) significantly increased perfusion
pressure, oxygen uptake, glucose uptake, and lactate release, all of
which were reversed by the addition of NP. 5-HT, on the other hand,
increased perfusion pressure and decreased oxygen uptake, of which NP
fully reversed only pressure but had no effect on glucose uptake and lactate efflux. Basal perfusion pressure, oxygen uptake, glucose uptake, and lactate efflux were found to have coefficient of variations (CV) of 16.1%, 10.7%, 43.8%, and 27.9%, respectively.
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Figure 3 shows the effect of the
vasomodulators on the microdialysis difference (Cout Cin) of unlabeled glucose and recovery of
[3H]glucose, as well as the calculated Cint
and arterial-interstitial (A Int) concentration difference for
glucose. The measured (Cout Cin)
difference was found to be unchanged across all the groups (Fig.
3A). On the other hand, the microdialysis recovery of
[3H]glucose was significantly increased by NE and ANG II
and decreased by 5-HT. These effects were fully reversed by NP after
ANG II and 5-HT but only partially reversed by NP after NE (Fig.
3B). The two type A vasoconstrictors increased the
interstitial concentration of glucose and 5-HT decreased it, each of
which was reversed by NP (Fig. 3C). As a consequence of
this, the (A Int) concentration difference was lowered by NE
and ANG II and elevated by 5-HT, and the vasoconstrictor-mediated
effects were blocked by NP (Fig. 3D). The CV of glucose
recovery and interstitial glucose concentration under basal conditions
were 22.0% and 11.5%, respectively.
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Figure 4 shows the effect of the
vasomodulators on the microdialysis (Cout Cin) difference of unlabeled lactate and recovery of
[14C]lactate, as well as Cint and (A Int) concentration difference for lactate. The concentration change
across the probe (Cout Cin) was
significantly reduced by the addition of NE and ANG II and increased by
5-HT (Fig. 4A). NP partially reversed the effects of ANG II
and 5-HT and fully reversed the effect of NE. The microdialysis recovery of [14C]lactate was increased by NE and ANG II
and decreased by 5-HT but only fully reversed by NP in the case of ANG
II and 5-HT (Fig. 4B). The interstitial concentration of
lactate was decreased by NE and ANG II and increased by 5-HT, each of
which was reversed by NP (Fig. 4C). Figure 4D
shows that NE and ANG II increased and 5-HT decreased the (A Int) concentration difference, whereas NP in the presence of the
vasoconstrictors returned all values to basal. The CV of lactate
recovery and interstitial lactate concentration under basal conditions
were 22.7% and 32.4%, respectively.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The important new data from this study are that the recovery of glucose and lactate increases with increased nutritive flow and decreases with increased nonnutritive flow in the perfused rat hindlimb. This is in the absence of changes in the total flow to muscle as assessed by 15-µm microsphere entrapment (8). The interstitial concentration of glucose and lactate was increased and decreased, respectively, by increasing nutritive flow with NE and ANG II (Figs. 3C and 4C). Decreasing nutritive flow with 5-HT, on the other hand, caused the opposite changes in interstitial concentration of glucose and lactate compared with NE and ANG II (Figs. 3C and 4C). For both glucose and lactate, however, the interstitial concentration approached that of the arterial concentration when nutritive flow was increased and diverged from the arterial concentration when nutritive flow was decreased (Figs. 3D and 4D).
Possible explanations for the changes in the recovery of glucose and lactate must focus on how the vasoconstrictors can influence the removal of [3H]glucose and [14C]lactate from the microdialysis probe. This is a similar concept to that previously published, in which the microdialysis O-to-I ratio of [14C]ethanol and 3H2O was affected by NE and 5-HT (27). It is likely that the two type A vasoconstrictors used in this study (NE and ANG II) increased the number of perfused capillaries or flow through capillaries adjacent to the probe because total flow to the muscle as assessed by 15-µm microspheres did not change (8). As a consequence of this, there would have been an increased removal of tracers from the probe, reflected by the increased recovery of [3H]glucose and [14C]lactate by NE and ANG II. This is consistent with previous studies showing that NE accesses a new vascular space in muscle (28) at the expense of nonnutritive flow that may be located in connective tissue (29) or nearby in muscle (5). The type B vasoconstrictor (5-HT), on the other hand, probably decreased the number of perfused capillaries or flow through capillaries adjacent to the probe without affecting total flow to the muscle (8). This would have resulted in decreased removal of the markers from the probe, reflected by a decreased recovery of [3H]glucose and [14C]lactate. Again, this is also consistent with previous studies showing that 5-HT denied access to a vascular space (28) and increased nonnutritive flow (5), possibly in the connective tissue (29).
The opposing changes of the interstitial concentration of glucose and lactate may also be explained with the concept of two vascular routes in muscle. During vasoconstriction with NE or ANG II, as the number of perfused capillaries increases, the blood is able to supply more glucose to and remove more lactate from the interstitial fluid around the muscle cells. Thus, even though the consumption of glucose is increased with NE and ANG II, the interstitial concentration is improved because of the greater capacity of the blood to supply glucose to the interstitial fluid surrounding the probe. Similarly, although the production and release of lactate has increased with NE and ANG II, the interstitial concentration is diminished because of the greater capacity of the blood flow around the probe to remove lactate.
Each muscle through which the probe traverses has a particular flow (volume flow/unit mass), with red muscles receiving a greater flow than white muscles (8). Under basal conditions, the flow to each muscle will be determined by the vascular resistance of that muscle because the pressure is stable and total flow is held constant by the pump. Despite an increase in vascular resistance during vasoconstriction, the blood flow to each muscle (as determined by 15-µm microspheres) remains the same (8). The distribution of flow within each muscle, however, will affect metabolism, with the two flow routes having variable vascular resistances. Under type B conditions, there would be vasoconstriction down to the level of the transverse arterioles with possible dilatation of nonnutritive vessels. The effect of this would be to decrease the resistance on nonnutritive (connective tissue) vessels to a greater degree than the nutritive vessels. Because total flow into the muscle remains constant, the flow must distribute preferentially into the nonnutritive pathway. Type A vasoconstriction, on the other hand, constricts at the terminal arteriole level, but those arterioles supplying the nonnutritive vessels would be constricted more than those supplying the nutritive vessels. Thus again, because total flow to the muscle is constant, the relatively lower resistance in the terminal arterioles supplying the nutritive vessels means they will receive a greater proportion of the flow.
The provision of extra glucose (and oxygen) by type A-mediated redistribution of blood flow may account for the increased metabolism of glucose, oxygen, and lactate. Further studies are needed to ascertain the degree to which this may occur as opposed to a paracrine signal released during redistribution of blood flow (6). These changes in blood flow distribution would lead to changes in vascular wall shear stress. If maintained over time in vivo, changes in vascular wall shear stress may be involved in vascular remodeling, for example, during exercise or periods of physical inactivity (7).
The lower glucose concentration in the interstitium compared with arterial plasma is consistent with that previously published (16, 21, 26, 30) except for one study that reported the same interstitial and arterial plasma concentration (11). The interstitial lactate concentration was previously reported to be <5 mM in vivo but consistently higher than the arterial plasma concentration (16, 19, 21, 23, 26). To our knowledge, however, this is the only report of absolute interstitial lactate concentration for perfused muscle. The lactate concentration reported in this study may be due to differences inherent in the perfused muscle model as well as increased glycolytic activity caused by damaged cells.
The interstitial fluid is in direct contact with skeletal muscle cells, and therefore the concentration of compounds in that space is important. It is not known, however, whether the interstitial concentration of compounds is controlled as opposed to being the net result of transport systems to and from the interstitial fluid. Interstitial lactate, for example, has been reported to be involved in the exercise pressor reflex (38) by stimulating group III and IV afferents that lie within the interstitial fluid (25). Stimulation of these afferents may be occurring under basal conditions because the concentration of lactate reported in the current study (8 mM) is comparable with that reported during exercise (21). However, recent studies in which the interstitial lactate concentration as well as muscle sympathetic nerve activity were measured suggest that lactate and H+ are not direct stimulators of group III and IV afferents (23, 24).
There is an extra complication in this study in that glucose uptake and lactate release were affected by NE and ANG II. It has been suggested that microdialysis recovery is affected by local metabolism and particularly cellular uptake (18, 39, 40). The muscle fiber types through which the probe passes would also be expected to affect the recovery because of their differences in vascularization and metabolic rates. Indeed, each fiber type would be expected to have its own intrinsic recovery for glucose and lactate that vasoconstrictor-mediated redistribution would affect to different degrees (the more highly vascularized red fibers would probably show a greater increase in recovery than white fibers). The overall probe recovery would reflect a weighted average of the recovery for each muscle through which the probe passed. Total blood flow to different muscles has been shown to be unaffected by the vasoconstrictors (8), but the degree of redistribution of blood flow and consequent metabolic changes are unknown. It is not possible, therefore, to determine the relative importance of each of the fiber types in this study.
Under 5-HT conditions, the decrease in recovery for glucose and lactate
would probably be due to the decrease in nutritive flow because there
was no change in metabolism for glucose and lactate. Under NE and ANG
II conditions, however, there was an increase in glucose uptake, which
means that there would be an increased rate of removal of glucose from
the interstitial pool. This would also mean that there would be a
greater removal of [3H]glucose from the interstitial
fluid and hence an increased [3H]glucose concentration
gradient between the microdialysis probe and the interstitial fluid.
Therefore, at least some of the increase in recovery during NE and ANG
II may be due to the increase in glucose uptake. The relative
contribution of metabolism, uptake, and nutritive blood flow require
further studies. The dependence of data obtained with the microdialysis
technique on the extent of nutritive flow and metabolism has important
implications. Although the microdialysis outflow-inflow concentration
difference (Cout Cin) does reflect the
interstitial concentration, the calculated interstitial concentration
will also depend on the recovery. The dependence on measuring recovery
can be avoided by the determination of the interstitial concentration
by the no-net flux or zero-flow methods, although these methods have
their own problems, particularly that of being time consuming (1,
2, 4). In the current study the (Cout Cin) difference for glucose was unchanged across all
conditions (Fig. 3A), but the calculated interstitial
concentration was affected by the vasoconstrictors (because they
affected the measured glucose recovery). The (Cout Cin) difference for lactate, on the other hand, was a good
indicator of interstitial concentration (Fig. 4). Therefore, any change
in total blood flow, nutritive blood flow, and metabolism would
necessitate the determination of the microdialysis recovery as well as
the (Cout Cin) difference under each
condition. Increased microdialysis glucose recovery has been reported
during exercise (21, 31), although it is not possible to
separate the effects of increased blood flow and increased metabolism
on glucose recovery in this case. One recent study using microdialysis
in muscle compared the recovery of D-glucose with the
nonmetabolized stereoisomer L-glucose when insulin was included in the dialysis medium (22). The authors reasoned
that only the D-glucose would be affected by alterations in
glucose uptake and metabolism by insulin. They found that the recovery of D-glucose increased by 50% in the presence of insulin,
whereas that of L-glucose was unchanged (22).
Because L-glucose recovery was unchanged, it is likely that
the insulin was unable to diffuse from the probe to nearby blood
vessels to affect total blood flow or capillary recruitment, which has
been shown to occur if insulin is supplied via the vasculature
(32).
In conclusion, the current study shows that the microdialysis recovery
of glucose and lactate and their respective interstitial concentration
are affected by alterations in the degree of nutritive blood flow as
well as changes in their metabolism. Changes to either of these
components would necessitate the determination of the recovery and
interstitial concentration under each condition. The determination of
the interstitial concentration appears to be of greater use than
relying on changes in the (Cout Cin) difference (assuming there is an appropriate analog available to
measure the recovery). The data support the concept that changes in the
distribution of blood flow within muscle affect the exchange of glucose
and lactate.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. M. B. Newman, Dept. of Biochemistry, Medical School, Univ. of Tasmania, GPO Box 252-58, Hobart 7001, Australia (E-mail: j.newman{at}utas.edu.au).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published March 7, 2002;10.1152/ajpheart.01024.2001
Received 27 November 2001; accepted in final form 27 February 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 compared with
vasoconstrictor.
